Nasopharyngeal carcinoma, a highly malignant tumor originated from nasopharyngeal epithelium, is very easy to invade the base of skull and other important structures, and its cervical lymph node metastasis and distant metastasis may occur earlier. Nasopharyngeal carcinoma is hard to be treated by surgery since it has high malignancy with a special pathogenic site. Therefore, nasopharyngeal carcinoma is clinically treated mainly by radiotherapy in combination with systemic chemotherapy. However, the traditional radiotherapy and chemotherapy have serious toxic and side effects, and the radiotherapy only applies to the primary tumor and its sentinel lymph node metastasis, but not to its distant metastasis. The five-year survival rate for nasopharyngeal carcinoma patients fluctuates around 60% due to limitation in the therapeutic method.
Monoclonal antibody drugs have shown a good prospect for clinical application in tumor therapy. A conjugate formed by a monoclonal antibody with a radionuclide, a drug or a toxin showed a targeting specific lethal role on tumor cell. In addition, some monoclonal antibodies specific for tumor markers themselves have significant antitumor effects. For example, Herceptin, an antibody to epidermal growth factor HER-2/neu of tumor cell, has achieved a good curative effect as a targeting drug for HER-2 positive metastatic breast cancer. However, monoclonal antibody still has several limitations in practical clinic application. It has a problem of immunogenicity, since most of monoclonal antibody drugs for clinical study are prepared by using mice. It does not have a good treatment effect on large volume of solid tumor due to its large molecular weight and low penetration into tumor. It has an extremely high production cost since the tumor treatment requires a large amount of antibody with high purity. The inhibition or killing of tumor cells which express a certain receptor only by using a monoclonal antibody does not mean a cure of tumor because of the heterogeneity of the tumor cells. Thus, it is difficult to achieve a desired effect for the treatment of nasopharyngeal carcinoma with high grade of malignancy only by using a monoclonal antibody as the targeting molecule.
Peptide, as a specific ligand to the molecule of a tumor marker, is the focus of researcher's attention. Peptide has advantages of small size, good tissue penetrability, low immunogenicity and low cost, compared with the monoclonal antibodies, and may overcome the defects of antibody preparation to a large extent. However, the in vivo application of targeting peptides is limited due to its relatively weak affinity to tumor and short half-life. Multivalent strategies based on nanotechnology can significantly prolong the effective circulation time of targeting peptides in vivo, and greatly improve its affinity for binding with a specific receptor, so as to achieve the purpose of significantly enhancing the biological effect of the peptide.
For this reason, an octavalent peptide fluorescent nano-probe based on tetramer far-red fluorescent protein was prepared by using a method for constructing a peptide fluorescent probe having multivalent and nanoscale effects found in our preliminary work. The tumor-targeting property and the biological anti-tumor effect of a peptide can be rapidly and accurately screened and identified by using the method. However, the clinical use of the far-red fluorescent protein is limited by its immunogenicity, because the far-red fluorescent protein is a foreign protein. Therefore, there is an urgent need to develop a nano-carrier capable of effectively transporting the targeted peptide without affecting its targeting property and therapeutic effect.
Nasopharyngeal carcinoma is a complex disease gradually developed from a multi-step interaction involving factors such as environmental factors and genetic genes of host. Clinical studies on the combined treatment with radiotherapy and adjuvant chemotherapy showed that a variety of anticancer drugs, either alone or in combination, have certain curative effect on nasopharyngeal carcinoma which is relatively sensitive to chemotherapy. The main water-soluble chemotherapeutic agents, such as cisplatin and 5-fluorouracil (5-FU), can significantly improve the prognosis of the patients. But regardless of alone or in combination, intravenously administered cisplatin and 5-FU have disadvantages of a short half-life and lack of selection, thereby increasing its toxic and side effects. Curcumin and paclitaxel are two kinds of representative anti-cancer herbal medicines. Curcumin, having many pharmacological effects, is a phenolic pigment extracted from the rhizome of Curcuma longa, a herbaceous plant. It is confirmed from many studies that curcumin can inhibit the growth of various tumor cells, and enhance the recruitment of NK cells in tumor microenvironment, thereby improving the body's immunity. Paclitaxel has been used in the treatment of advanced nasopharyngeal carcinoma, since it was first approved by FDA of US to enter into the clinic treatment of ovarian cancer in 1992. It has been found that paclitaxel can also enhance the recruitment of NK cells in tumor microenvironment and activate antigen presenting ability of dendritic cells, so as to enhance the immune responses against tumor cells. Because both curcumin and paclitaxel are fat-soluble drugs, they are difficult to be directly taken up by tumor tissue cells via passive transportation, and have highly toxic and side effects in a vein, and thus have poor clinic applications currently. So far, a targeted therapeutic nano-drug for nasopharyngeal carcinoma has not been reported in China.
Nano-carrier is an effective means for targeted delivery of an imaging contrast agents or a drug to tumor cells to achieve specific imaging diagnosis and targeted treatment of tumor. A high-density lipoprotein-like peptide-lipid nanoparticle has been invented (International Publication Number: WO2009073984). It is formed by interacting a functional peptide R4F having a α-helix structure with phospholipid and cholesteryl ester, and has a particle size of 30 nm or less. Such nanoparticle mainly targets to cells with high expression of scavenger receptor B (SR-B1) based on the function of the peptide. However, since SR-B1 is also highly expressed in the normal tissue cells (e.g. liver cells), the nanoparticle does not have a desired contrast in distribution between tumors and normal tissues, and may have potential toxic and side effects during transportation of chemotherapy drugs. In addition, the nanoparticle of WO2009073984 only functions as a tool for targeted delivery, and does not involve in the effects of tumor therapy.
In summary, it is necessary to develop a ultra-small particle-size (<40 nm) nanoparticle carrying a dual-targeted therapeutic peptide and simultaneously loading with an imaging contrast agent and a chemotherapy drug to be used for highly specific synchronous diagnosis and therapy of nasopharyngeal carcinoma, which will become a targeted nano-drug for nasopharyngeal carcinoma with great potential in clinical application.